DNA damage, gene expression, growth arrest and cell death.

The sequence of biochemical and molecular events that mediate growth arrest and cell death in tumor cells exposed to agents that induce DNA damage is poorly defined. This commentary exploits the recent explosion of information regarding oncogenes, tumor suppressor genes, and cell-cycle regulatory genes to develop a model for growth arrest/cell death. The model focuses on changes in the expression of these genes, in the level and phosphorylation of their protein products, and in the interaction(s) between these proteins. It is recognized that such a model is, of necessity, incomplete, since new gene functions associated with the cellular response to DNA damage will continuously be uncovered; in addition, the proposed sequence of events will likely require modification as the relationships between the functions of the discrete gene products are clarified. Nevertheless, it is hoped that this commentary will provide a conceptual framework within which to fit currently available information as well as future findings relating to the expression and function of DNA-damage-responsive genes, and that the sections of the model that are incomplete will provide a springboard for the development of research approaches designed to answer specific questions regarding the nature of the cellular response to DNA damage.